The redevelopment/regeneration pattern of amputated limbs from a blastema in salamander suggests that enhanced regeneration might be achieved by mimicking the developmental microenvironment. Inspired by the discovery that the expression of magnesium transporter‐1 (MagT1), a selective magnesium (Mg) transporter, is significantly upregulated in the endochondral ossification region of mouse embryos, a Mg‐enriched 3D culture system is proposed to provide an embryonic‐like environment for stem cells. First, the optimum concentration of Mg ions (Mg 2+ ) for creating the osteogenic microenvironment is screened by evaluating MagT1 expression levels, which correspond to the osteogenic differentiation capacity of stem cells. The results reveal that Mg 2+ selectively activates the mitogen‐activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway to stimulate osteogenic differentiation, and Mg 2+ influx via MagT1 is profoundly involved in this process. Then, Mg‐enriched microspheres are fabricated at the appropriate size to ensure the viability of the encapsulated cells. A series of experiments show that the Mg‐enriched microenvironment not only stimulates the osteogenic differentiation of stem cells but also promotes neovascularization. Obvious vascularized bone regeneration is achieved in vivo using these Mg‐enriched cell delivery vehicles. The findings suggest that biomaterials mimicking the developmental microenvironment might be promising tools to enhance tissue regeneration.

BackgroundTo cope with the limitations faced by autograft acquisitions particularly for multiple nerve injuries, artificial nerve conduit has been introduced by researchers as a substitute for autologous nerve graft for the easy specification and availability for mass production. In order to best mimic the structures and components of autologous nerve, great efforts have been made to improve the designation of nerve conduits either from materials or fabrication techniques. Electrospinning is an easy and versatile technique that has recently been used to fabricate fibrous tissue-engineered scaffolds which have great similarity to the extracellular matrix on fiber structure.ResultsIn this study we fabricated a collagen/poly(ε-caprolactone) (collagen/PCL) fibrous scaffold by electrospinning and explored its application as nerve guide substrate or conduit in vitro and in vivo. Material characterizations showed this electrospun composite material which was made of submicron fibers possessed good hydrophilicity and flexibility. In vitro study indicated electrospun collagen/PCL fibrous meshes promoted Schwann cell adhesion, elongation and proliferation. In vivo test showed electrospun collagen/PCL porous nerve conduits successfully supported nerve regeneration through an 8 mm sciatic nerve gap in adult rats, achieving similar electrophysiological and muscle reinnervation results as autografts. Although regenerated nerve fibers were still in a pre-mature stage 4 months postoperatively, the implanted collagen/PCL nerve conduits facilitated more axons regenerating through the conduit lumen and gradually degraded which well matched the nerve regeneration rate.ConclusionsAll the results demonstrated this collagen/PCL nerve conduit with tailored degradation rate fabricated by electrospinning could be an efficient alternative to autograft for peripheral nerve regeneration research. Due to its advantage of high surface area for cell attachment, it is believed that this electrospun nerve conduit could find more application in cell therapy for nerve regeneration in future, to further improve functional regeneration outcome especially for longer nerve defect restoration.

affect the quality of life of patients. [2] Unlike the external cutaneous membrane, the lining of the oral cavity has a wet and highly dynamic environment, [3] with endogenous saliva and exogenous food and drink continuously bathing the oral mucosa. In addition, chewing, speech, swallowing, and even changes in facial expressions cause movement of the tongue and oral mucosa. These complex challenges typically render local treatment strategies for protective materials and therapeutic drugs ineffective, owing to their short retention on the mucosal surface. [4] Topical agents such as solutions, powders, ointments, polymer films, and hydrogels (e.g., Gengigel) commonly used in clinical settings are diluted or washed away by saliva within 1 h. This is far shorter than the optimal repair time for treating oral mucosal disorders, which require 12-24 h to heal. [4] In addition to meet the fundamental requirements of safety and usability, the ideal oral mucosal repair material should be thin, elastic, and have excellent wet-tissue adhesion to resist The wet and highly dynamic environment of the mouth makes local treatment of oral mucosal diseases challenging. To overcome this, a photo-crosslinking hydrogel adhesive is developed inspired by the success of light-curing techniques in dentistry. The adhesive operates on a fast (within 5 s) phototriggered S-nitrosylation coupling reaction and employs imine anchoring to connect to host tissues. Unlike other often-used clinical agents that adhere weakly and for short durations, this thin, elastic, adhesive, and degradable cyclic o-nitrobenzyl-modified hyaluronic acid gel protects mucosal wounds from disturbance by liquid rinsing, oral movement, and friction for more than 24 h. The results from both rat and pig oral mucosa repair models demonstrate that this new gel adhesive creates a favorable microenvironment for tissue repair and can shorten tissue healing time. This study thus illustrates a therapeutic strategy with the potential to advance the treatment of oral mucosal defects in the clinic.

Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6-CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future.

Dentin‐pulp complex regeneration is a promising alternative treatment for the irreversible pulpitis caused by tooth trauma or dental caries. This process mainly relies on the recruitment of endogenous or the transplanted dental pulp stem cells (DPSCs) to guide dentin‐pulp tissue formation. Platelet‐derived growth factor (PDGF), a well‐known potent mitogenic, angiogenic, and chemoattractive agent, has been widely used in tissue regeneration. However, the mechanisms underlying the therapeutic effects of PDGF on dentin‐pulp complex regeneration are still unclear. In this study, we tested the effect of PDGF‐BB on dentin‐pulp tissue regeneration by establishing PDGF‐BB gene‐modified human dental pulp stem cells (hDPSCs) using a lentivirus. Our results showed that PDGF‐BB can significantly enhance hDPSC proliferation and odontoblastic differentiation. Furthermore, PDGF‐BB and vascular endothelial growth factor (VEGF) secreted by hDPSCs enhanced angiogenesis. The chemoattractive effect of PDGF‐BB on hDPSCs was also confirmed using a Transwell chemotactic migration model. We further determined that PDGF‐BB facilitates hDPSCs migration via the activation of the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway. In vivo, CM‐DiI‐labeled hDPSCs were injected subcutaneously into mice, and our results showed that more labeled cells were recruited to the sites implanted with calcium phosphate cement scaffolds containing PDGF‐BB gene‐modified hDPSCs. Finally, the tissue‐engineered complexes were implanted subcutaneously in mice for 12 weeks, the Lenti‐PDGF group generated more dentin‐like mineralized tissue which showed positive staining for the DSPP protein, similar to tooth dentin tissue, and was surrounded by highly vascularized dental pulp‐like connective tissue. Taken together, our data demonstrated that the PDGF‐BB possesses a powerful function in prompting stem cell‐based dentin‐pulp tissue regeneration. Stem Cells Translational Medicine 2017;6:2126–2134

Electrospun scaffolds have been broadly studied to enhance bone regeneration because of the ability to simulate the structure and biological functions of the extracellular matrix. Polydopamine (PDA) is used to coat various surfaces at a slightly basic pH (8–8.5) and spontaneously reacts with nucleophilic functional groups. It is suitable for surface modifications of scaffolds correlated with bone formation. E7 is a newly discovered peptide with specific affinity for bone marrow mesenchymal stem cells (BMSCs). It can be useful for recruiting stem cells. Here, electrospun silk fibroin (SF) scaffolds were fabricated, and PDA was used for surface modification followed by grafting E7 (SF–PDA–E7). These composite SF–PDA–E7 electrospun scaffolds improved hydrophilicity, facilitated cell proliferation and adhesion, and boosted the osteogenic differentiation of BMSCs by creating osteoinduction conditions under the synergistic effects of PDA and E7. Moreover, the scaffolds showed high efficiency for recruiting BMSCs induced by E7 both in vitro and in vivo, which was associated with the SDF-1α/CXCR4 axis and the p38, extracellular signal-related kinase, and Akt signal transduction pathways. These functionalized electrospun scaffolds promoted regeneration of bone in the rat calvarial bone defect model. In general, this study verified that PDA could be a simple and efficient method for surface modification, and E7-grafted PDA-modified SF electrospun scaffolds were suitable for bone tissue engineering.

Cells are transplanted to regenerate an organs' parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite common use of decellularized matrix, little is known what pivotal signals must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and VEGF. Contrasting to modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma involving VEGF signaling, but also parenchymal dentin via Wnt/β-catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells extending processes into newly-formed dentin with structure-mechanical He et al.

There is an increased use of nanophase titanium dioxide (TiO(2)) in bone implants and scaffolds. However, nano-debris is generated at the bone-biomaterial interface. Therefore, TiO(2) nanoparticles (NPs) of many sizes were investigated for cytotoxic effects on murine MC3T3-E1 preosteoblasts. These TiO(2) NPs induced a time- and dose-dependent decrease in cell viability. There was a significant increase in lactate dehydrogenase (LDH) release, apoptosis and mitochondrial membrane permeability following short-term exposure of the cells to TiO(2) NPs. These NPs also increased granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) gene expression. Compared with the 32 nm TiO(2) NPs, 5 nm TiO(2) NPs were more toxic, induced more apoptosis, increased mitochondrial membrane permeability and stimulated more GM-CSF expression at a high concentration (≥100 μg/ml). The results implied that the differential toxicity was associated with variations in size, so more attention should be given to the toxicity of small NPs for the design of future materials for implantation.